Scientists may soon be able to influence muscle formation more easily as a result of research conducted in the National Institute of Arthritis and Musculoskeletal and Skin Diseases’ Laboratory of Muscle Biology. The researchers there and at institutions in California and Italy have found that inhibitors of the enzyme deacetylase can switch the pathway of muscle precursor cells (myoblasts) from simply reproducing themselves to becoming mature cells that form muscle fibers (myotubules).

It has been known for some time that deacetylase prevents the skeletal muscle gene from being expressed, which inhibits myoblasts from forming muscle. The research team has found that under certain conditions, deacetylase inhibitors (DIs) in myoblasts enhance muscle gene expression and muscle fiber formation.

Knowledge of how DIs act against deacetylase is providing important insights on potential ways to correct problems that occur during embryonic muscle development. This research may also lead to methods to induce muscle growth, regeneration and repair in adults.

Simona Iezzi, Ph.D., and Vittorio Sartorelli, M.D., in the NIAMS Muscle Gene Expression Group, along with Pier Lorenzo Puri, M.D., at the Salk Institute for Biological Studies and other investigators at the University of Rome, exposed human and mouse myoblasts to DIs while they were dividing or after placement in a medium that stimulates myoblasts to become muscle cells. The researchers found that exposing dividing human and mouse myoblasts to a DI increased the levels of muscle proteins and led to a dramatic increase in the formation of muscle fibers. Similar experiments were done in developing mouse embryos, resulting in an increased number of somites (the regions of the embryo from which muscle cells are derived) and augmented expression of muscle genes.

Dr. Sartorelli’s group continues to investigate how the myoblasts are stimulated to fuse into myotubules. One theory is that the performance of poorly differentiated myoblasts is enhanced when they are recruited by cells with a good capacity to differentiate. Further research will be directed at discovering whether the cells that have been induced to form muscle will restore muscle function when transplanted into a mouse model of muscular dystrophy. In addition, the researchers at the NIAMS Muscle Gene Expression Group plan to expose adult muscle stem cells from a mouse model to DIs to understand their biology and their potential use as therapeutic tools.

Scientists have discovered that a group of chemicals known as Histone Deacetylase (HDAC) inhibitors stimulate growth and regeneration of adult skeletal muscle cells by increasing expression of the protein follistatin. The research, published in the May issue of Developmental Cell, may provide new avenues for developing effective means to promote regeneration in muscular dystrophies.

Dr. Vittorio Sartorelli from the Muscle Gene Expression Group in the Laboratory of Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, in Bethesda, Maryland, and colleagues at the Salk Institute and the Dulbecco Telethon Institute in Rome report that HDAC inhibitors, which stimulate the formation of mature muscle cells from immature precursor cells, also cause a significant elevation of follistatin levels. When follistatin levels are reduced, then HDAC inhibitors no longer stimulate adult muscle growth. The regeneration activities of the HDAC inhibitors appear to function only in skeletal muscle, since follistatin is not stimulated in other cell types tested. In animal studies, administration of an HDAC inhibitor produced clear signs of muscle regeneration in regions of injured skeletal muscle tissues.

“Our findings establish for the first time that follistatin promotes the recruitment and fusion of immature muscle cells to pre-existing adult muscle fibers. These results suggest that follistatin is a promising target for future drug development of muscle regeneration. HDAC inhibitors, by stimulating follistatin, could well be pharmacologically useful as stimulants of muscle regeneration. We are investigating whether these inhibitors are a viable treatment to regenerate healthy new muscle tissues in animal models of muscular dystrophies,” explains Dr. Sartorelli. The functional link between HDAC inhibitors, follistatin, and adult muscle regeneration is especially provocative as an HDAC inhibitor is already being used clinically in humans as an anti-cancer therapeutic.

Experts at The University of Nottingham are to investigate the effect of nutrients on muscle maintenance in the hope of determining better ways of keeping up our strength as we get old.

The researchers, based at the School of Graduate Entry Medicine and Health in Derby, want to know what sort of exercise we can take and what food we should eat to slow down the natural loss of skeletal muscle with ageing.

The team from the Department of Clinical Physiology, which has over 20 years experience in carrying out this type of metabolic study, need to recruit 16 healthy male volunteers in two specific age groups to help in it’s research.

Skeletal muscles make up about half of our body weight and are responsible for controlling movement and maintaining posture. However, at around 50 years of age our muscles begin to waste at approximately 0.5 per cent to one per cent a year. It means that an 80 year old may only have 70 per cent of the muscle of a 50 year old.

Since the strength of skeletal muscle is proportional to muscle size, such wasting makes it harder to carry out daily activities requiring strength, such as climbing stairs and leads to a loss of independence and an increased risk of falls and fractures.

In order for skeletal muscles to maintain their size, the large reservoirs of muscle protein require constant replenishment in the way of amino acids from protein contained within the food we eat. In fact, amino acids from our food act not only as the building blocks of muscle proteins but also actually ‘tell’ our muscle cells to build proteins.

Recent research from the clinical physiology team has shown that the cause of muscle wasting with ageing appears to be an attenuation of muscle building in response to protein feeding. In other words, as we age we lose the ability to covert the protein in the food we eat in to muscle tissue. The proposed research will investigate the mechanisms responsible for this deficit.

Dr Philip Atherton, who is currently recruiting volunteers, said: “I am really excited to be involved in this project because if we can determine ways to better maintain muscle mass as we age it will greatly benefit us all.”

The researchers are looking for 16 healthy, non-smoking, male volunteers aged 18 to 25 and 65 to 75.

Initially, the volunteers will undergo a health screening and then on a different day, under the supervision of a doctor, will be infused with an amino acid mixture to simulate feeding along with a ‘tagged’ amino acid that allows them to assess muscle building. To make these measures, blood samples will be taken from the arm and muscle biopsies from the thigh muscle under local anaesthesia. Volunteers will receive an honorarium to cover their expenses.